1. Field of the Invention
This invention relates to microporous membranes, and more particularly to surface modified microporous membranes suitable for the filtration of aqueous fluids, such as biological liquids.
2. Prior Art
Microporous membranes are well known in the art. For example, U.S. Pat. No. 3,876,738 to Marinaccio et al. (1975) describes a process for preparing a microporous membrane, for example, by quenching a solution of a film forming polymer in a non-solvent system for the polymer. European patent application No. 0 005 536 to Pall (1979) describes a similar process.
Commercially available microporous membranes, for example, made of nylon, are available from Pall Corporation, Glen Cove, N. Y. under the trademark "ULTIPOR N.sub.66 ". Such membranes are advertised as useful for the sterile filtration of pharmaceuticals, e.g. removal of microorganisms.
Various studies in recent years, in particular Wallhausser, Journal of Parenteral Drug Association, Jun., 1979, Vol. 33, #3, pp. 156-170, and Howard et al, Journal of the Parenteral Drug Association, Mar.-Apr., 1980, Volume 34, #2, pp. 94-102, have reported the phenomena of bacterial breakthrough in filtration media, in spite of the fact that the media had a low micrometer rating. For example, commercially available membrane filters for bacterial removal are typically rated as having an effective micrometer rating for the microreticulate membranes structure of 0.2 micrometers or less, yet such membrane typically have only a 0.357 effective micrometer rating for spherical contaminant particles, even when rated as absolute for Ps. diminuta, the conventional test for bacterial retention. This problem of passage of a few microorganisms under certain conditions has been rendered more severe as the medical uses of filter membranes has increased.
One method of addressing this problem is to prepare a tighter filter having a sufficiently small effective pore dimension to capture microorganisms, etc., by mechanical sieving. Such microporous membranes of 0.1 micrometer rating or less may be readily prepared but flow rates at conventional pressure drops are prohibitively low. Increasing the pressure drop to provide the desired flow rate is not generally feasible because pressure drop is an inverse function of the fourth power of pore diameter.
It has long been recognized that adsorptive effects can enhance the capture of particulate contaminants. For example, Wenk, "Electrokinetic and Chemical Aspects of Water Filtration", Filtration and Separation, May/Jun. 1974, indicates that surfactants, pH, and ionic strength may be used in various ways to improve the efficiency of a filter by modifying the charge characteristics of either the suspension, filter or both.
It has also been suggested that adsorptive sequestration (particle capture within pore channels), may sometimes be more important in sterile filtration than bubble point characterization of internal geometry (representing the "largest pore"). See, e.g., Tanny et al, Journal of the Parenteral Drug Association, Nov.-Dec. 1978, Vol. 21, #6, pp. 258-267 and Jan.-Feb., 1979, Vol. 33, #1, pp. 40-51 and Lukaszewicz et al, Id., Jul.-Aug., 1979, Vol. 33, #4, pp. 187-194.
Pall et al, Colloids and Surfaces 1 (1980), pp. 235-256, indicates that if the zeta potential of the pore walls of a membrane, e.g. nylon 66, and of the particles are both low, or if they are oppositely charged, the particle will tend to adhere to the pore walls, and the result will be removal of particles smaller than the pores of the filter. Pall et al suggest the use of membranes of substantially smaller pore size to increase the probability of obtaining microbial sterility in filtering fluids.
Zierdt, Applied and Environmental Microbiology, Dec. 1979, pp. 1166-1172, found a strong adherence by bacteria, yeast, erythrocytes, leukocytes, platelets, spores and polystyrene spheres to membrane materials during filtration through membranes with pore-size diameters much larger than the particles themselves. Zierdt found that cellulose membranes adsorbed more bacteria, blood cells and other particles than did polycarbonate filters. Of lesser adsorptive capacity were vinyl acetate, nylon, acrylic and Teflon membranes. Zierdt additionally found that solvent cast membrane filter materials, e.g. nylon, had strong surface charges, whereas ordinary fibrous cellulose materials which are not solvent cast do not.
Attempts to increase the short life of filter media due to pore blockage and enhance flow rates through filter media having small pores have been made by charge modifying the media by various means to enhance capture potential of the filter. For example, U.S. Pat. Nos. 4,007,113 and 4,007,114 to Ostreicher, describe the use of a melamine formaldehyde cationic colloid to charge modify fibrous and particulate filter elements; U.S. Pat. No. 4,305,782, to Ostreicher et al describes the use of an inorganic cationic colloidal silica to charge modify such elements; and U.S. Ser. No. 164,797, filed Jun. 30, 1980, to Ostreicher et al, describes the use of a polyamido-polyamine epichlorhydrin cationic resin to charge modify such filter elements. None of these references teaches or suggests charge modifying a synthetic organic polymeric microporous membrane, nor do any of the filtration media described therein, e.g. fiber and/or particulate, provide the advantages of such a membrane.
Similarly, U.S. Pat. Nos. 3,242,073 (1966) and 3,352,424 (1967) to Guebert et al, describe removal of micro-organisms from fluids by passage through a filter medium of conventional anionic type filter aid, e.g. diatomaceous earth, paper filter pulp, fullers earth, charcoal, etc., having an adsorbed cationic, organic, polyelectrolyte coating. The coated filter aid media is said to possess numerous cationic sites which are freely available to attract and hold particles bearing a negative surface charge.
U.S. Pat. No. 4,178,438 to Hasset et al (1979) describes a process for the purification of industrial effluent using cationically modified cellulose containing material, e.g., bleached or unbleached pine sulphite cellulose, kraft sulphate cellulose, paper, cardboard products, textiles fibers made of cotton, rayon staple, jute, woodfibers, etc. The cationic substituent is bonded to the cellulose via a grouping --O--CH.sub.2 --N--, where the nitrogen belongs to an amide group of the cationic part and the oxygen to the cellulose part.
There are numerous references which describe the treatment of porous membranes for various objects. U.S. Pat. No. 3,556,305 to Shorr (1971) describes a tripartite membrane for use in reverse osmosis comprising an anisotropic porous substrate, an ultra-thin adhesive layer over the porous substrate, and a thin diffusive membrane formed over the adhesive layer and bound to the substrate by the adhesive layer. Such anisotropic porous membranes are distinguished from isotropic, homogeneous membrane structures used for microfiltration whose flow and retention properties are independent of flow direction and which do not function properly when utilized in the invention of Shorr.
U.S. Pat. No. 3,556,992 to Massuco (1971) describes another anisotropic ultra-filtration membrane having thereon an adhering coating of irreversibly compressed gel.
U.S. Pat. No. 3,808,305 to Gregor (1974) describes a charged membrane of macroscopic homogeneity prepared by providing a solution containing a matrix polymer, polyelectrolytes (for charge) and a crosslinking agent. The solvent is evaporated from a cast film which is then chemically cross-linked. The membranes are used for ultrafiltration.
U.S. Pat. Nos. 3,944,485 (1976) and 4,045,352 (1977) to Rembaum et al describe ion exchange hollow fibers produced by introducing into the wall of the pre-formed fiber, polymerizable liquid monomers which are then polymerized to form solid, insoluble, ion exchange resin particles embedded within the wall of the fiber. The treated fibers are useful as membranes in water treatment, dialysis and generally to separate ionic solutions. See also U.S. Pat. No. 4,014,798 to Rembaum (1977).
U.S. Pat. No. 4,005,012 to Wrasidlo (1977) describes a process for producing a semi-permeable anisotropic membrane useful in reverse osmosis processes. The membranes are prepared by forming a polymeric ultra-thin film, possessing semi-permeable properties by contacting an amine modified polyepihalohydrin with a polyfunctional agent and depositing this film on the external surface of a microporous substrate. Preferred semi-permeable membranes are polysulfone, polystyrene, cellulose butyrate, cellulose nitrate and cellulose acetate.
U.S. Pat. No. 4,125,462 to Latty (1978) describes a coated semi-permeable reverse osmosis membrane having an external layer or coating of a cationic polyelectrolyte preferably poly(vinylimidazoline) in the bi-sulfate form.
U.S. Pat. No. 4,214,020 to Ward et al (1980) describes a novel method of coating the exteriors of a bundle of hollow-fiber semi-permeable membranes for use in fluid separations. Typical polymers coated are polysulfones, polystyrenes, polycarbonates, cellulosic polymers, polyamides and polyimides. Numerous depositable materials are listed, see col. 10, lines 55 - col. 12, for example, poly(epichlorhydrin) or polyamides.
U.S. Pat. No. 4,239,714 to Sparks et al (1980) describes a method of modifying the pore size distribution of a separation media to provide it with a sharp upper cut-off of a preselected molecular size. This is accomplished by effectively blocking the entrances to all of the pores larger than a preselected desired cut-off size, but leaving unchanged the smaller pores. The separation media may be in the form of polymeric membranes, e.g. cellulose acetate, cellulose nitrate, polycarbonates, polyolefins, polyacrylics, and polysulfones. The pores are filled with a volatile liquid which is evaporated to form voids at the pore entrances and a concentrated solution of a crosslinkable or polymerizable pore blocking agent, such as protein, enzyme, or polymeric materials is then applied to the surface of the membrane.
U.S. Pat. No. 4,250,029 to Kiser et al (1981) describes coated membranes having two or more external coatings of polyelectrolytes with at least one oppositely charged adjacent pair separated by a layer of material which is substantially charge neutralized. Kiser et al is primarily directed to the use of charged membranes to repel ions and thereby prevent passage through the membrane pores. The coated membranes are described as ordinary semi-permeable membranes used for ultrafiltration, reverse osmosis, electrodialysis or other filtration processes. A microscopic observation of the coated membranes shows microscopic hills and valleys of polyelectrolyte coating formed on the original external smooth skin of the membrane. The membranes are particularly useful for deionizing aqueous solutions. Preferred membranes are organic polymeric membranes used for ultrafiltration and reverse osmosis processes, e.g., polyimide, polysulfone, aliphatic and aromatic nylons, polyamides, etc. Preferred membranes are anisotropic hollow fiber membranes having an apparent pore diameter of from about 21 to about 480 angstroms.
Charge modified microporous filter membranes are disclosed in U.S. Ser. No. 358,822 of Ostreicher, filed May 9, 1973, now abandoned (corresponding to Japanese Pat. No. 923,649 and French Pat. No. 74 15733). As disclosed therein, an isotropic cellulose mixed ester membrane, was treated with a cationic colloidal melamine-formaldehyde resin to provide charge functionality. The membrane achieved only marginal charge modification. Additionally, the membrane was discolored and embrittled by the treatment, extractables exceeded desirable limits for certain critical applications, and the membrane was not thermally sanitizable or sterilizable. Ostreicher also suggests such treatment for the nylon membranes prepared by the methods described in U.S. Pat. No. 3,783,894 to Lovell (1957) and U.S. Pat. No. 3,408,315 to Paine (1968). It has been demonstrated that nylon microporous membranes treated according to said Ostreicher reference would also demonstrate marginal charge modification, high extractables and/or inability to be thermally sanitizable or sterilizable.
The aforesaid Ostreicher U.S. Ser. No. 314,307 (published as PCT 0050804 on May 5, 1982) generally describes a novel cationic charge modified microporous membrane comprising a hydrophilic organic polymeric microporous membrane and a charge modifying amount of a primary cationic charge modifying agent bonded to substantially all of the internal microstructure of the membrane. The primary charge modifying agent is a water-soluble organic polymer having a molecular weight greater than about 1,000 wherein each monomer thereof has at least one epoxide group capable of bonding to the surface of the membrane and at least one tertiary amine or quaternary ammonium group. Preferably, a portion of the epoxy groups on the organic polymer are bonded to a secondary charge modifying agent selected from the group consisting of:
(i) aliphatic amines having at least one primary amino or at least two secondary amino groups; and
(ii) aliphatic amines having at least one secondary amino and a carboxyl or hydroxyl substituent.
The membrane is made by a process for cationically charge modifying a hydrophilic organic polymeric microporous membrane by applying to the membrane the aforesaid charge modifying agents, preferably by contacting the membrane with aqueous solutions of the charge modifying agents. The preferred microporous membrane is nylon, the preferred primary and secondary charge modifying agents are, respectively, polyamido-polyamine epichlorohydrin and tetraethylene pentamine. The charge modified microporous membrane may be used for the filtration of fluids, particularly parenteral or biological liquids. The membrane has low extractables and is sanitizable or sterilizable.
The aforesaid Chu et al Ser. No. 566,764 generally describes a novel anionic charge modified microporous membrane comprising a hydrophilic organic polymeric microporous membrane and a charge modifying amount of anionic charge modifying agent bonded to substantially all of the membrane microstructure. The anionic charge modifying agent is preferably a water-soluble polymer having anionic functional groups, e.g. carboxyl, phosphonous, phosphonic and sulfonic groups. The charged membrane is made by a process of applying the anionic charge modifying agent to the membrane, preferably by contacting the membrane with aqueous solutions of the charge modifying agent.
The just described applications describe a comparatively complex treatment of a preformed membrane requiring treatment, rinse and drying steps which involve complicated equipment and expensive capital investment.